Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

Mrinal M. Gounder; Albiruni Abdul Razak; Neeta Somaiah; Sant Chawla; Javier Martin-Broto; Giovanni Grignani; Scott M. Schuetze; Bruno Vincenzi; Andrew J. Wagner; Bartosz Chmielowski; Robin L. Jones; Richard F. Riedel; Silvia Stacchiotti; Elizabeth T. Loggers; Kristen N. Ganjoo; Axel Le Cesne; Antoine Italiano; Xavier Garcia Del Muro; Melissa Burgess; Sophie Piperno-Neumann; Christopher Ryan; Mary F. Mulcahy; Charles Forscher; Nicolas Penel; Scott Okuno; Anthony Elias; Lee Hartner; Tony Philip; Thierry Alcindor; Bernd Kasper; Peter Reichardt; Lore Lapeire; Jean Yves Blay; Christine Chevreau; Claudia Maria Valverde Morales; Gary K. Schwartz; James L. Chen; Hari Deshpande; Elizabeth J. Davis; Garth Nicholas; Stefan Gröschel; Helen Hatcher; Florence Duffaud; Antonio Casado Herráez; Roberto Diaz Beveridge; Giuseppe Badalamenti; Mikael Eriksson; Christian Meyer; Margaret Von Mehren; Brian A. Van Tine; Katharina Götze; Filomena Mazzeo; Alexander Yakobson; Aviad Zick; Alexander Lee; Anna Estival Gonzalez; Andrea Napolitano; Mark A. Dickson; Dayana Michel; Changting Meng; Lingling Li; Jianjun Liu; Osnat Ben-Shahar; Dane R. Van Domelen; Christopher J. Walker; Hua Chang; Yosef Landesman; Jatin J. Shah; Sharon Shacham; Michael G. Kauffman; Steven Attia

doi:10.1200/JCO.21.01829

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

Mrinal M. Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M. Schuetze, Bruno Vincenzi, Andrew J. Wagner, Bartosz Chmielowski, Robin L. Jones, Richard F. Riedel, Silvia Stacchiotti, Elizabeth T. Loggers, Kristen N. Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-NeumannChristopher Ryan, Mary F. Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K. Schwartz, James L. Chen, Hari Deshpande, Elizabeth J. Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A. Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A. Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R. Van Domelen, Christopher J. Walker, Hua Chang, Yosef Landesman, Jatin J. Shah, Sharon Shacham, Michael G. Kauffman, Steven Attia

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSEAntitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.METHODSSEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461).RESULTSTwo hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P =.011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P <.0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P =.001).CONCLUSIONPatients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Original language	English (US)
Pages (from-to)	2479-2490
Number of pages	12
Journal	Journal of Clinical Oncology
Volume	40
Issue number	22
DOIs	https://doi.org/10.1200/JCO.21.01829
State	Published - Aug 1 2022

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1200/JCO.21.01829

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Gounder, M. M., Razak, A. A., Somaiah, N., Chawla, S., Martin-Broto, J., Grignani, G., Schuetze, S. M., Vincenzi, B., Wagner, A. J., Chmielowski, B., Jones, R. L., Riedel, R. F., Stacchiotti, S., Loggers, E. T., Ganjoo, K. N., Le Cesne, A., Italiano, A., Garcia Del Muro, X., Burgess, M., ... Attia, S. (2022). Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Clinical Oncology, 40(22), 2479-2490. https://doi.org/10.1200/JCO.21.01829

Gounder, MM, Razak, AA, Somaiah, N, Chawla, S, Martin-Broto, J, Grignani, G, Schuetze, SM, Vincenzi, B, Wagner, AJ, Chmielowski, B, Jones, RL, Riedel, RF, Stacchiotti, S, Loggers, ET, Ganjoo, KN, Le Cesne, A, Italiano, A, Garcia Del Muro, X, Burgess, M, Piperno-Neumann, S, Ryan, C, Mulcahy, MF, Forscher, C, Penel, N, Okuno, S, Elias, A, Hartner, L, Philip, T, Alcindor, T, Kasper, B, Reichardt, P, Lapeire, L, Blay, JY, Chevreau, C, Valverde Morales, CM, Schwartz, GK, Chen, JL, Deshpande, H, Davis, EJ, Nicholas, G, Gröschel, S, Hatcher, H, Duffaud, F, Herráez, AC, Beveridge, RD, Badalamenti, G, Eriksson, M, Meyer, C, Von Mehren, M, Van Tine, BA, Götze, K, Mazzeo, F, Yakobson, A, Zick, A, Lee, A, Gonzalez, AE, Napolitano, A, Dickson, MA, Michel, D, Meng, C, Li, L, Liu, J, Ben-Shahar, O, Van Domelen, DR, Walker, CJ, Chang, H, Landesman, Y, Shah, JJ, Shacham, S, Kauffman, MG & Attia, S 2022, 'Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial', Journal of Clinical Oncology, vol. 40, no. 22, pp. 2479-2490. https://doi.org/10.1200/JCO.21.01829

@article{c4867da602a145f1a13cccd73b012c5a,

title = "Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial",

abstract = "PURPOSEAntitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.METHODSSEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461).RESULTSTwo hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P =.011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P <.0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P =.001).CONCLUSIONPatients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.",

author = "Gounder, {Mrinal M.} and Razak, {Albiruni Abdul} and Neeta Somaiah and Sant Chawla and Javier Martin-Broto and Giovanni Grignani and Schuetze, {Scott M.} and Bruno Vincenzi and Wagner, {Andrew J.} and Bartosz Chmielowski and Jones, {Robin L.} and Riedel, {Richard F.} and Silvia Stacchiotti and Loggers, {Elizabeth T.} and Ganjoo, {Kristen N.} and {Le Cesne}, Axel and Antoine Italiano and {Garcia Del Muro}, Xavier and Melissa Burgess and Sophie Piperno-Neumann and Christopher Ryan and Mulcahy, {Mary F.} and Charles Forscher and Nicolas Penel and Scott Okuno and Anthony Elias and Lee Hartner and Tony Philip and Thierry Alcindor and Bernd Kasper and Peter Reichardt and Lore Lapeire and Blay, {Jean Yves} and Christine Chevreau and {Valverde Morales}, {Claudia Maria} and Schwartz, {Gary K.} and Chen, {James L.} and Hari Deshpande and Davis, {Elizabeth J.} and Garth Nicholas and Stefan Gr{\"o}schel and Helen Hatcher and Florence Duffaud and Herr{\'a}ez, {Antonio Casado} and Beveridge, {Roberto Diaz} and Giuseppe Badalamenti and Mikael Eriksson and Christian Meyer and {Von Mehren}, Margaret and {Van Tine}, {Brian A.} and Katharina G{\"o}tze and Filomena Mazzeo and Alexander Yakobson and Aviad Zick and Alexander Lee and Gonzalez, {Anna Estival} and Andrea Napolitano and Dickson, {Mark A.} and Dayana Michel and Changting Meng and Lingling Li and Jianjun Liu and Osnat Ben-Shahar and {Van Domelen}, {Dane R.} and Walker, {Christopher J.} and Hua Chang and Yosef Landesman and Shah, {Jatin J.} and Sharon Shacham and Kauffman, {Michael G.} and Steven Attia",

note = "Funding Information: Supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by Karyopharm Therapeutics, Inc, assisted in the preparation of this manuscript in accordance with Good Publication Practice (GPP3) guidelines. Funding Information: Research Funding: Karyopharm Inc, AADI, Eli-Lilly, National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA008748) Publisher Copyright: {\textcopyright} American Society of Clinical Oncology.",

year = "2022",

month = aug,

day = "1",

doi = "10.1200/JCO.21.01829",

language = "English (US)",

volume = "40",

pages = "2479--2490",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "22",

}

TY - JOUR

T1 - Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma

T2 - A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

AU - Gounder, Mrinal M.

AU - Razak, Albiruni Abdul

AU - Somaiah, Neeta

AU - Chawla, Sant

AU - Martin-Broto, Javier

AU - Grignani, Giovanni

AU - Schuetze, Scott M.

AU - Vincenzi, Bruno

AU - Wagner, Andrew J.

AU - Chmielowski, Bartosz

AU - Jones, Robin L.

AU - Riedel, Richard F.

AU - Stacchiotti, Silvia

AU - Loggers, Elizabeth T.

AU - Ganjoo, Kristen N.

AU - Le Cesne, Axel

AU - Italiano, Antoine

AU - Garcia Del Muro, Xavier

AU - Burgess, Melissa

AU - Piperno-Neumann, Sophie

AU - Ryan, Christopher

AU - Mulcahy, Mary F.

AU - Forscher, Charles

AU - Penel, Nicolas

AU - Okuno, Scott

AU - Elias, Anthony

AU - Hartner, Lee

AU - Philip, Tony

AU - Alcindor, Thierry

AU - Kasper, Bernd

AU - Reichardt, Peter

AU - Lapeire, Lore

AU - Blay, Jean Yves

AU - Chevreau, Christine

AU - Valverde Morales, Claudia Maria

AU - Schwartz, Gary K.

AU - Chen, James L.

AU - Deshpande, Hari

AU - Davis, Elizabeth J.

AU - Nicholas, Garth

AU - Gröschel, Stefan

AU - Hatcher, Helen

AU - Duffaud, Florence

AU - Herráez, Antonio Casado

AU - Beveridge, Roberto Diaz

AU - Badalamenti, Giuseppe

AU - Eriksson, Mikael

AU - Meyer, Christian

AU - Von Mehren, Margaret

AU - Van Tine, Brian A.

AU - Götze, Katharina

AU - Mazzeo, Filomena

AU - Yakobson, Alexander

AU - Zick, Aviad

AU - Lee, Alexander

AU - Gonzalez, Anna Estival

AU - Napolitano, Andrea

AU - Dickson, Mark A.

AU - Michel, Dayana

AU - Meng, Changting

AU - Li, Lingling

AU - Liu, Jianjun

AU - Ben-Shahar, Osnat

AU - Van Domelen, Dane R.

AU - Walker, Christopher J.

AU - Chang, Hua

AU - Landesman, Yosef

AU - Shah, Jatin J.

AU - Shacham, Sharon

AU - Kauffman, Michael G.

AU - Attia, Steven

N1 - Funding Information: Supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by Karyopharm Therapeutics, Inc, assisted in the preparation of this manuscript in accordance with Good Publication Practice (GPP3) guidelines. Funding Information: Research Funding: Karyopharm Inc, AADI, Eli-Lilly, National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA008748) Publisher Copyright: © American Society of Clinical Oncology.

PY - 2022/8/1

Y1 - 2022/8/1

N2 - PURPOSEAntitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.METHODSSEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461).RESULTSTwo hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P =.011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P <.0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P =.001).CONCLUSIONPatients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

AB - PURPOSEAntitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.METHODSSEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461).RESULTSTwo hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P =.011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P <.0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P =.001).CONCLUSIONPatients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

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UR - http://www.scopus.com/inward/citedby.url?scp=85129787816&partnerID=8YFLogxK

U2 - 10.1200/JCO.21.01829

DO - 10.1200/JCO.21.01829

M3 - Article

C2 - 35394800

AN - SCOPUS:85129787816

SN - 0732-183X

VL - 40

SP - 2479

EP - 2490

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 22

ER -

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

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